Optically active carboalkylated amino alcohols and their utilization in optical resolution

ABSTRACT

A carboalkylated amino alcohol having each of the below shown formulae is novel and optically active. A separating agent comprising the alcohol and a support is effectively useful to separate a variety of racemates for example with chromatography. The alcohol may be chemically or physically combined with the support. ##STR1## [wherein Ph represents a phenyl group, R represents a hydrogen atom, an alkyl group having the carbon number of 1 to 10, or an aryl group having the carbon number of 6 to 10, X represents an --O-- group or a --S-- group, and Z represents a hydrogen atom, an alkyl group having the carbon number of 1 to 10 or a metal element].

This is a division of Ser. No. 06/946,460, filed Dec. 24, 1986 now U.S.Pat. No. 4,966,985.

FIELD OF THE INVENTION

The present invention relates to novel optically active carboalkylatedamino alcohols, separating agents comprising them, and a method foroptical resolution.

In more detail, the present invention relates to novel optically activecarboalkylated amino alcohol isomers, novel optically active separatingagents consisting of a support and one of the optically activecompounds, and a method for optical resolution by the novel separatingagent. The novel separating agents in the present invention can be usedas stationary phases for column chromatography which separatesracemates. The separating agent is called also an absorbent.

BACKGROUND OF THE INVENTION

It is known that for a conventional separating agent; in which anoptically active compound is fixed on an inorganic support or an organicpolymer support, natural amino acids are used as a source material ofthe optically active compound except for the following examples.

The exceptional examples are artificial amino acids such asphenylglycine and tertiary-leucine, basic and acidic compounds derivedfrom natural amino acids and tartaric acid, and 1-arylethylamines. Theexceptional examples are disclosed in the following literatures: Journalof Chromatography [V. A. Davankov et al, Vol. 82, page 352 (1973)];Journal of Chromatography [C. Cubiron et al, Vol. 204, page 185 (1981)];Chromatographia [V. A. Davancov et al, Vol. 13, page 677 (1980)];Journal of High Resolution Chromatography and ChromatographyCommunication [G. Guvitz et al, Vol. 2, page 145 (1979)]. Moreover,examples using an basic compound, derived from an artificial or naturalamino acid such as phenylglycine or tertiary-leucine, Journal ofChromatography [W. H. Pirkle et al, Vol. 192, page 143 (1980)] andChromatographia [V. A. Davankov et al, Vol. 13, page 399 (1980)] areknown.

The present inventors have accomplished the present invention as theresult of various investigations on the improvement of the resolvingability of conventional separating agents in optical resolution. Namely,conventional separating agents having an optically active compound havebeen used as the stationary phases for column chromatography in order toresolve racemates optically. However, when a natural amino acid, anartificial amino acid, a basic or acidic compound derived from them,tartaric acid, or 1-arylethylamine is used as the optically activecompound, the racemates that are possible to be optically resolved arelimited. Therefore, a new chiral stationary phase, which can be appliedto the optical resolution of wide-ranging racemates, is needed.

SUMMARY OF THE INVENTION

It is the primary object of the present invention to provide noveloptically active carboalkylated amino alcohols represented by thefollowing general formulae (1-1), (1-2), (1-3), and (1-4), respectively.

It is the second object of the present invention to provide noveloptically active separating agents consisting of a support and one ofthe optically active compounds represented by the following generalformulae (2-1), (2-2), (2-3) and (2-4), respectively.

It is the third object of the present invention to provide a method forthe optical resolution of racemates. ##STR2## [wherein Ph represents aphenyl group, R represents a hydrogen atom, an alkyl group having thecarbon number of 1 to 10, or an aryl group having the carbon number of 6to 10, X represents an --O-- group or a --S-- group, and Z represents ahydrogen atom, an alkyl group having the carbon number of 1 to 10 or ametal element

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have investigated intensively to find out newoptically active compounds applicable as reagents for asymmetricsynthesis and/or separating agents for optical resolution, and haveaccomplished the present invention. The separating agent in the presentinvention can separate racemates which can not be separated by aconventional separating agent.

The first invention relates to novel optically active carboalkylatedamino alcohols represented by the following general formulae (1-1),(1-2), (1-3) and (1-4).

The second invention relates to novel optically active separating agentsconsisting of a support and one of the optically active amino alcoholshaving the above shown formulae (2-1), (2-2), (2-3) and (2-4),respectively.

The third invention relates to a method for the optical resolution usingthe novel optically active separating agents.

The compositions of the present invention are described as follows.

The optically active carboalkylated amino alcohols in the firstinvention include the following concrete modes. Namely, R represents ahydrogen atom, an alkyl group having the carbon number of 1 to 10, or anaryl group having the carbon number of 6 to 10, X represents an --O--group or a --S-- group, and Z represents a hydrogen atom, an alkyl grouphaving the carbon number of 1 to 10 or a metal element in the generalformulae (1-1), (1-2), (1-3) and (1-4).

More specifically, R represents a hydrogen atom, a methyl group, anethyl group, a phenyl group, a tolyl group or a naphthyl group, thealkyl for Z is methyl or ethyl and the metal element is copper, zinc,nickel, iron, cobalt, magnesium, calcium, sodium, potassium, etc.(Synthesis of optically active carboalkylated amino alcohols)

The optically active carboalkylated amino alcohols in the presentinvention can be prepared according to the following methods.

In the first method, erythro-2-amino-1,2-diphenylethanols, namely,(1S,2R)-2-amino-1,2-diphenylethanol [formula (3-1)] and(1R,2S)-2-amino-1,2-diphenylethanol [formula (3-2)] are used as astarting material. Moreover, threo-isomers,(1R,2R)-2-amino-1,2-diphenylethanol [formula (3-3)] and(1S,2S)-2-amino-1,2-diphenylethanol [formula (3-4)], which can beconverted from (1S,2R)- and (1R,2S)-forms, respectively, are also usedas a starting material. ##STR3## [wherein Ph represents a phenyl group]

Each optically active isomer described above is alkylated by acarbomethylating agent such as ethyl bromoacetate or by acarboalkylating agent such as ethyl 2-chloropropionate. Then, the esterpart is converted to metallic salt such as sodium carboxylate orcarbothiolate with sodium hydroxide or sodium hydrosulfide,respectively. Moreover, other metallic salts can be obtained via thecorresponding carboxylic acid or carbothioic acid.

For example, when (1S,2R)-2-amino-1,2-diphenylethanol is alkylated withethyl bromoacetate and converted to the sodium salt, the reaction stepsare as shown in the following scheme. ##STR4## [wherein Ph represents aphenyl group]

In another method, racemic erythro-2-amino-1,2-diphenylethanol orthreo-2-amino-1,2-diphenylethanol is used as a starting material.Carboalkylation followed by hydrolysis gave racemic carboalkylated aminoalcohol, which can be separated into the corresponding enatiomers byoptical resolution.

Moreover, the optically active materials in the present invention can besynthesized not only by the methods described above but also by thering-opening reaction of optically active trans-stilbene oxide withalkyl glycinate or alaninate followed by hydrolysis.

The precursors for the optically active materials in the presentinvention can be also obtained by the optical resolution of the reactionproduct of racemic trans- or cis-stilbene oxide with alkyl glycinate oralaninate. (support)

The supports, used in the present invention, are organic or inorganiccompounds such as polystyrene, polyamide, polyacrylate,polymethacrylate, silica-gel, almina, and glass beads. Moreover,mixtures and composites of these materials, and reaction products withother elements can be used as a support.

The supports are preferably used in the form of particles, the size ofwhich is 0.1 to 1000 micrometer, preferably 1 to 100 micrometer.Supports which are microporous with a large total area are preferable,and suitable pore sizes are 10 Å to 10000 Å. However, a suitable ratioof pore size to particle size is less than 1/10.

The separating agent of the present invention can be produced by fixing,chemically or physically, one of the optically active carboalkylatedamino alcohols with a support through, or not through, a spacer.

The amount of the optically active compound may be 0.1 to 100 w/w % ofthe support, preferably 1 to 10 w/w %.

Specific methods are described below.

Optically active carboalkylated amino alcohols, which are characteristicin the present invention, are prepared as described before. Theseoptically active materials are preferred to have high optical purity butare not necessarily pure.

Moreover, as described below, to fix the optically active materialchemically on the support, a variety of synthetic processes can beapplied. Therefore, the method for the preparation of the opticallyactive part is not restricted only to those mentioned before.

A spacer is an agent combining the support and the optically activematerial in the present invention.

For example, when an inorganic support such as silica-gel, alumina, andglass beads is used as a support, many kinds of silane coupling reagentscan be used. Moreover, the following spacers can also be used; materialswhich have more than two reactive functions and can react withoutdamaging the optical activity of the optical active compoundsrepresented by general formulae (2-1), (2-2), (2-3), and (2-4); andmonofunctional materials which have comparatively intensive interactionwith the support and can react without the damage mentioned above. Asthe reactive functions in the multifunctional spacers, carboxylic acid,carboxylic anhydride, acyl halide, ester, halide, and epoxide functionsare satisfactory. Aldehyde and imine functions are also applicable.Moreover, monocarboxylic acids, monohalides, and monoepoxides having analiphatic long chain are effective as a monofunctional spacer.

The methods for the chemical fixation of the optically active compoundsrepresented by above mentioned general formulae (2-1), (2-2), (2-3), and(2-4), on the support are as follow.

One of the methods is the direct fixation of the optically activecompounds on silica-gel, treated with a silane coupling reagent, or onan organic polymer having a reactive functional group. For example, whenthe support has an epoxy group, the amino group in the optically activecompounds can react with the support by ring-opening. The acylation ofthe amino group with carboxylic acids or their derivatives, thealkylation of the amino group with halides, the tosylation of the aminogroup with tosyl halides, and the carbamoylation of the amino group withisocyanates are also useful to fix the optically active compounds on thesupport. A typical example is shown in the following reaction scheme(4). After carboalkylation of (1S,2R)-2-amino-1,2-diphenylethanol withethyl bromoacetate, the ester part is converted to the sodium salt withaq. sodium hydroxide. Then, the salt is allowed to react with theglycidyl group of silica-gel treated with3-glycidoxypropyltrimethoxysilane. The product is changed to thecorresponding copper salt. ##STR5## [wherein Ph represents a phenylgroup, Y represents silica-gel, m and n is an integer, m+n is 3]

In another method, an inorganic support is allowed to react with thesilane coupling reagent bonded previously with one of the opticallyactive compounds represented by the general formulae (2-1), (2-2), (2-3)and (2-4).

Moreover, separating agents can be prepared by the homo- orco-polymerization of polymerizable compounds bonded previously with oneof the optically active compounds represented by the general formulae(2-1), (2-2), (2-3), and (2-4). The examples of the polymerizable parentcompounds are p-(chloromethyl)styrene, glycidyl acrylate, glycidylmethacrylate, acrylic acid and its derivatives, and methacrylic acid andits derivatives.

Moreover, to fix the above mentioned optically active compounds on aninorganic support or on an organic polymer support, the reaction stepscan be reversed. Namely, in the first step, the amino group of2-amino-1,2-diphenylethanol is allowed to react with a spacer, asupport, or a polymerizable compound. Then, the reaction product isalkylated with a carboalkylating agent such as ethyl bromoacetate andethyl 2-chloropropionate. In the third step, the product of the secondstep is converted to a metallic salt.

For example, (1S,2R)-2-amino-1,2-diphenylethanol is allowed to reactwith 3-glycidoxypropyltrimethoxysilane. After N-alkylation with ethylbromoacetate, the ester part is converted to a sodium salt with aq.sodium hydroxide. The salt is combined with silica-gel by chemicalreaction and converted to a copper salt. The reaction steps arepresented in scheme (5). ##STR6## [wherein Ph represents a phenyl group,Y represents silica-gel, m and n is an integer and m+n is 3]

The method for the physical fixation of the optically active compoundson the support is as follows.

A hydrophobic group such as a long chain alkyl is introduced into theoptically active compounds represented by above mentioned generalformulae (2-1), (2-2), (2-3) and (2-4), and the modified compounds areadsorbed on silica-gel or activated carbon given a hydrophobic nature,or on an organic polymer having a hydrophobic group.

The optically active separating agents are applicable for the opticalresolution by chromatography such as gas chromatography, liquidchromatography, and thin layer chromatography.

With respect to application to liquid chromatography or thin layerchromatography, all solvents except for those which can dissolve theseparating agent and/or to react with it, can be used as an eluent.Moreover, there is no limitation, except for reactive liquids, in thecase of the separating agent, in which the optically active compound isfixed chemically with the support or is insolubilized by cross-linking.But, it is preferable to check many kinds of eluents because theresolving ability of the separating agent changes depending on theeluent.

EXAMPLES

The following examples illustrate preferred embodiments of the presentinvention, which by no means limit the invention.

Capacity factor (K'), separation factor (α) and resolution factor (Rs)are calculated according to the following equetions, respectively.##EQU1##

EXAMPLE 1 synthesis of(1R,2S)-2-ethoxycarbonylmethylamino-1,2-diphenylethanol

(1R,2S)-2-amino-1,2-diphenylethanol (2.10 g) was dissolved indichloromethane (30 ml) and stirred at room temperature. Ethylbromoacetate (2.00 g), dissolved in dichloromethane (15 ml), was addedto the solution. The mixture was stirred at room temperature for 7 days,and then triethylamine (1.5 ml) was added and stirred at roomtemperature for an additional day. After the spot of the startingmaterial in TLC disappeared, dichloromethane was evaporated underreduced pressure. Benzene (100 ml) was added to the remaining residue,and the triethylamine hydrobromide salt was washed out with water. Theorganic layer was washed with brine and dried over anhydrous sodiumsulfate. The solution was filtered and evaporated. The residue (2.60 g,88%) was recrystallized from hexane (ca. 300 ml). The crystals depositedwere collected and dried under reduced pressure. Yield 2.20 g (75%); mp123°-125° C.; [α]_(D) ¹⁸ +2.4° (c 1.00, EtOH). IR (KBr): 3180, 1745,765, 705 cm.sup. -1. ¹ H-NMR (CDCl₃): 1.17 (t, 3H, J=7 Hz), 2.35 (bs,2H), 3.16 (pseudo s, 2H), 3.98 (q, 2H, J=7 Hz), 4.15 (d, 1H, J=6 Hz),4.76 (d, 1H, J=6 Hz), 7.20 (s, 10H) ppm.

Analytically calculated for C₁₈ H₂₁ NO₃ : C, 72.22; H, 7.07; N, 4.68.Found: C, 72.43; H, 7.11; N, 4.47.

EXAMPLE 2 synthesis of(1S,2R)-2-ethoxycarbonylmethylamino-1,2-diphenylethanol

(1S,2R)-2-amino-1,2-diphenylethanol (3.15 g) was dissolved indichloromethane (45 ml) and stirred at room temperature. Ethylbromoacetate (3.0 g), dissolved in dichloromethane (15 ml), was added tothe solution. The mixture was stirred at room temperature for 7 days,and then triethylamine (2.31 ml) was added and stirred at roomtemperature for an additional day. After the spot of the startingmaterial in TLC disappeared, dichloromethane was evaporated underreduced pressure. Benzene (100 ml) was added to the remaining residue,and the triethylamine hydrobromide salt was washed out with water. Theorganic layer was washed with brine and dried over anhydrous sodiumsulfate. The solution was filtered and evaporated. The residue (3.41 g,77%) was recrystallized from hexane (ca. 300 ml). The crystals depositedwere collected and dried under reduced pressure. Yield 3.25 g (73%); mp126.5°-127° C.; [α]_(D) ²² -2.5° (c 1.01, EtoH). IR and ¹ H-NMR spectra,and Rf value of the product are completely identical with those of(1R,2S)-form mentioned in Example 1.

EXAMPLE 3 synthesis of (1S,2R)-2-carboxymethylamino-1,2-diphenylethanolmono sodium salt

(1S,2R)-2-ethoxycarbonylmethylamino-1,2-diphenylethanol (2.02 g) wassuspended in methanol (20 ml), and 1M sodium hydroxide (6.8 ml) wasadded with stirring. After the suspension was stirred at roomtemperature for 3 days, the precipitate was completely dissolved. Thesolution was evaporated and dried in vacuo (about 2 mm Hg) at 70° C. for12 h. Yield 1.92 g (97%), mp 229°˜234° C. (decomp.), [α]_(D) ¹⁶ -3.7 (c0.76, H₂ O). IR (KBr): 3280, 1600, 1415, 760, 700 cm⁻¹.

EXAMPLE 4 synthesis of (1R,2S)-2-carboxymethylamino-1,2-diphenylethanolmono sodium salt

(1R,2S)-2-ethoxycarbonylmethylamino-1,2-diphenylethanol (2.60 g) wassuspended in methanol (20 ml), and 1M sodium hydroxide (8.6 ml) wasadded with stirring. After the suspension was stirred at roomtemperature for 3 days, the precipitate was completely dissolved. Thesolution was evaporated and dried in vacuo (about 2 mm Hg) at 70° C. for12 h. Yield 2.47 g (97%), mp 231°-235° C. (decomp.), [α]_(D) ¹⁷ +3.8° (c0.83, H₂ O). IR (KBr): 3280, 1600, 1415, 760, 700 cm⁻¹.

EXAMPLE 5 synthesis of (1S,2R)-2-carboxymethylamino-1,2-diphenylethanol

1.55 g of (1S,2R)-2-carboxymethylamino-1,2-diphenylethanol mono sodiumsalt was dissolved in 40 ml of water and 1.2M hydrochloric acid wasadded to adjust the pH at 8. The precipitated crystals were washed 2times with water and 2 times with methanol. The washed crystals weredried under reduced pressure (about 2 mm Hg) at 70° C. for 12 h. Mp250°-251.5° C. (decomp.); [α]_(D) ²¹ -3.4° (c 1.00, 1H NaOH). IR (KBr):3320, 3050, 2890, 1625, 1570, 1390, 760, 710, 700 cm⁻¹.

Analytically calculated for C₁₆ H₁₇ NO₃ : C, 70.83; H, 6.32; N, 5.16.Found: C, 70.54; H, 6.14; N, 5.05.

EXAMPLE 6 synthesis of (1R,2S)-2-carboxymethylamino-1,2-diphenylethanol

2.50 g of (1R,2S)-2-carboxymethylamino-1,2-diphenylethanol mono sodiumsalt was dissolved in 60 ml of water and 1.2M hydrochloric acid wasadded to adjust the pH at 8. The precipitated crystals were washed 2times with water and 2 times with methanol. The washed crystals weredried under reduced pressure (about 2 mm Hg) at 70° C. for 12 h. Yield1.95 g (84%); mp 249°-251° C. (decomp.); [α]_(D) ²¹ +3.3 (c 1.00, 1MNaOH). IR (KBr): 3320, 3050, 2890, 1625, 1570, 1390, 760, 710, 700 cm⁻¹(the spectrum is identical with that of (1S,2R)-form).

EXAMPLE 7 synthesis of(1S,2S)-2-ethoxycarbonylmethylamino-1,2-diphenylethanol

(1S,2S)-2-amino-1,2-diphenylethanol (526 mg) was dissolved indichloromethane (10 ml) and stirred at room temperature. Ethylbromoacetate (412 mg), dissolved in dichloromethane (3 ml), was added tothe solution. The mixture was stirred at room temperature for 5 days,and then triethylamine (0.4 ml) was added and stirred at roomtemperature for an additional day. After the spot of the startingmaterial in TLC disappeared, dichloromethane was evaporated underreduced pressure. Benzene (100 ml) was added to the residue, and thesolution was worked up. The crude product (2.9 g) was purified by silicagel column chromatography using dichloromethane/methanol (19/1) as aneluent, to give the pure product as oil. Yield 614 mg (83%); [α]_(D) ¹⁷-33.8° (c 1.03, MeOH). IR (neat): 3350, 1740, 1205, 765, 705 cm⁻¹. ¹H-NMR (CDCl₃): 1.20 (t, 3H, J=7 Hz), 3.02 (bs, 2H), 3.66 (d, 1H, J=8Hz), 4.07 (q, 2H, J=7 Hz), 4.59 (d, 1H, J=8 Hz), 7.05 (s, 10H) ppm.Analytically calculated for C₁₈ H₂₁ NO₃ : C, 72.22; H, 7.07; N, 4.68.Found: C, 72.48; H, 7.21; N, 4.42.

EXAMPLE 8 synthesis of (1S,2S)-2-carboxymethylamino-1,2-diphenylethanolmono sodium salt

(1S,2S)-2-ethoxycarbonylmethylamino-1,2-diphenylethanol (450 mg) wasdissolved in methanol (10 ml), and 1M sodium hydroxide (1.6 ml) wasadded with stirring. The mixture was stirred at room temperature for 12h, and then evaporated and dried in vacuo (about 2 mm Hg) at 70° C. for12 h. Yield 421 mg (96%); mp 222°-225° C. (decomp.); [α]_(D) ¹⁸ -43.3°(c 1.06, MeOH). IR (KBr): 3305, 1590, 1415, 770, 700 cm⁻¹.

EXAMPLE 9 synthesis of (1S,2S)-2-carboxylmethylamino-1,2-diphenylethanol

296 mg of (1S,2S)-2-carboxymethylamino-1,2-diphenylethanol mono sodiumsalt was suspended in 50 ml of water, and 1.2M hydrochloric acid wasadded to adjust the pH at 8.

After the solution was stirred for 2 hours, precipitated crystals werefiltered and washed 2 times with water to give 213 mg (79%) of crude(1S, 2S)-2-carboxymethylamino-1,2-diphenylethanol.

The crude crystals were recrystallized from water, and 167 mg (62%) of(1S,2S)-2-carboxymethylamino-1,2-diphenylethanol was obtained. Mp226°-228° C. (decomp.); [α]_(D) -52.1° (c 1.02, 1M NaOH/MeOH=1/1). IR(KBr): 3270, 3120, 1610, 1385, 1075, 765, 705 cm⁻¹. Analyticallycalculated for C₁₆ H₁₇ NO₃ : C, 70.83; H, 6.32; N, 5.16. Found: C,70.59; H, 6.21; N, 5.32.

EXAMPLE 10 Production of a separating agent combined with(1R,2S)-2-carboxymethylamino-1,2-diphenylethanol mono sodium salt

To a suspension of 7.0 g of silica-gel, Lichrosorbs:100, a tradename ofthe product being available from E. Merck, having a size of 10 microns,having dried for 3 h at 120° C. in 50 ml of dry benzene, 3.5 ml of3-glycidoxypropyltrimethoxysilane was added. Then the suspension wasrefluxed for 8 h with removal of methanol formed from the mixture. Aftercooling, the benzene was removed by filtration, and the silica-gel wassuspended in methanol (20 ml). Then, the mono sodium salt of(1R,2S)-2-carboxymethylamino-1,2-diphenylethanol obtained in Example 4was added. The mixture was shaken for 3 days at the room temperature.The silica-gel was collected by filtration, washed with methanol andpoured into a copper (II) sulfate solution. The copper-loaded chiralseparating agent was collected by filtration and washed successivelywith water and the mobile phase. A possible structure of the obtainedchiral separating agent is shown below. ##STR7##

EXAMPLE 11

Example 10 was followed except that(1S,2S)-2-carboxymethylamino-1,2-diphenylethanol mono-sodium saltobtained in Example 8 was instead used. A possible structure of theobtained chiral separating agent is shown below. ##STR8##

EXAMPLE 12

Example 10 was followed except that(1S,2R)-2-carboxymethylamino-1,2-diphenylethanol mono-sodium saltobtained in Example 3 was instead used. A possible structure of theobtained separating agent is below shown. ##STR9##

EXAMPLE 13

The separating agent obtained in Example 10 was packed into a stainlesssteel of a column having a length of 25 cm and an internal diameter of0.46 by the ascending slurry method.

The chromatography was taken at 30° C. at a flow rate of 1.00 ml perminute, using a 0.25 mM solution of copper (II) sulfate as the mobilephase. Results in the resolution of amino acids, amino acid derivativesand hydroxy acids are shown in Table 1.

EXAMPLE 14

The resultion was carried out in the same way as in Example 13, insteadusing the separating agent obtained in Example 11. Results are shown inTable 2.

EXAMPLE 15

A separating agent was prepared, using(1R,2R)-2-amino-1,2-diphenylethanol, in the same way as shown inExamples 7, 8 and 11. A possible structure of the obtained separatingagent is shown below. ##STR10##

                  TABLE 1                                                         ______________________________________                                                                 separation                                                                              resolution                                 racemic     capacity factor                                                                            factor    factor                                     compound    K'.sub.d K'.sub.l                                                                              α R.sub.s                                  ______________________________________                                        DL-leucine  10.4     14.4    1.35    1.83                                     DL-methionine                                                                             11.3     13.6    1.21    1.25                                     DL-arginine 10.9     13.6    1.25    1.50                                     hydrochloride                                                                 DL-alanine  6.24      7.61   1.22    1.36                                     DL-glutamine                                                                              8.13     10.1    1.24    1.53                                     DL-glutamic acid                                                                          8.86     11.1    1.25    0.84                                     DL-citrulline                                                                             9.24     11.7    1.27    1.54                                     DL-ornitine 8.03      9.84   1.23    0.99                                     hydrochoride                                                                  DL-proline  8.08     18.0    2.22    3.49                                     DL-lysine   7.81      9.73   1.25    1.16                                     hydrochloride                                                                 DL-tyrosine 12.2     10.3    1.19    1.20                                     DL-tryptophane                                                                            19.6     16.4    1.19    1.25                                     DL-mandelic acid                                                                          3.52      4.43   1.26    0.91                                     DL-N-acetyl 4.29      5.00   1.17    --                                       tryptophane                                                                   DL-N-CBZ-   8.77     11.4    1.30    --                                       phenylalanine                                                                 DL-lactic acid                                                                            3.13      4.32   1.38    --                                       DL-indolinic acid*                                                                        25.1     38.4    1.53    3.00                                     DL-tropic acid**                                                                          6.08      7.34   1.21    1.38                                     DL-phenylalaninic                                                                         --       --      --      1.45                                     acid amide                                                                    ______________________________________                                         *Flow rate 1.5 ml/minute(at 50° C.)                                    **Flow rate 0.8 ml/minute(at 40° C.)                              

                  TABLE 2                                                         ______________________________________                                                                 separation                                                                              resolution                                 racemic     capacity factor                                                                            factor    factor                                     compound    K'.sub.d K'.sub.l                                                                              α R.sub.s                                  ______________________________________                                        DL-threonine                                                                              5.89     7.71    1.31    1.74                                     DL-tyrosine 12.0     9.87    1.22    --                                       DL-phenylalanine                                                                          11.1     9.80    1.22    --                                       DL-citrulline                                                                             9.40     10.02   1.09    --                                       DL-aspartic acid                                                                          4.34     5.04    1.16    --                                       DL-serine   5.48     6.36    1.16    --                                       DL-indolinic acid*                                                                        17.14    28.5    1.66    2.31                                     DL-tropic acid**                                                                          2.35     3.51    1.49    1.60                                     ______________________________________                                         *Flow rate 1.5 ml/minute(at 50° C.)                                    **Flow rate 0.8 ml/minute(at 40° C.)                              

What is claimed is:
 1. A separating agent which comprises a supportcombined with one of the optically active components having the formulae( 2-1), (2-2), (2-3) and (2-4), respectively: ##STR11## in which Ph isphenyl, R is hydrogen, an alkyl having 1 to 10 carbon atoms or an arylhaving 6 to 10 carbon atoms, X is a group of --O-- or --S-- and Z ishydrogen, an alkyl having 1 to 10 carbon atoms or a metal elementselected from the group consisting of copper, iron, zinc, nickel,cobalt, magnesium, calcium, sodium and potassium.
 2. A separating agentas claimed in claim 1, in which R is hydrogen, X is a group of --O-- andZ is hydrogen, methyl, ethyl, copper, iron, zinc, nickel, cobalt,magnesium, calcium, sodium or potassium.
 3. A separating agent asclaimed in claim 1, in which said support is chemically combined withsaid optically active component.
 4. A separating agent as claimed inclaim 1, in which said support is chemically combined with saidoptically active component through a spacer.
 5. A separating agent asclaimed in claim 1, in which said support is physically combined withsaid component.
 6. A separating agent as claimed in claim 1, in whichsaid support is an organic or inorganic substance.
 7. A separating agentas claimed in claim 1, in which said support is silica-gel.
 8. Aseparating agent as claimed in claim 4, in which said spacer is a silanecoupling reagent.
 9. A separating agent as claimed 1, in which theoptical active component has the formula: ##STR12##
 10. A separatingagent as claimed in claim 1, in which said optically active componenthas the formula: ##STR13##
 11. A separating agent as claimed in claim 1,in which said optically active component has the formula: ##STR14## 12.A separating agent as claimed in claim 1, in which said optically activecomponent has the formula: ##STR15##
 13. A separating agent as claimedin claim 4, in which said spacer is glycidoxypropylsilane.